Apolipoprotein A-I (ApoA-I) is the most abundant protein (70%) of high-density lipoprotein (HDL), whose concentration is known to be inversely correlated with cardiovascular risk. HDL-associated ApoA-I plays a crucial role in cholesterol homeostasis by regulating reverse cholesterol transport and delivering it to the liver (Yancey et al; 2003, Arterioscler. Thromb. Vasc. Biol. 23:712-719). HDL-associated ApoA-I also has anti-inflammatory properties and has antioxidant properties.
High levels of auto-antibodies to ApoA-I of IgG subclass (anti-ApoA-I IgG) have been described in patients suffering from systemic lupus erythematosus (SLE), an autoimmune condition associated with a high cardiovascular disease (CV) risk (Dinu et al, 1998, Lupus 7:355-360). Anti-ApoA-I IgG auto-antibodies have also been described in other high CV risk populations including myocardial infarction (MI) patients (Vuilleumier et al, 2010a, Eur. Heart J. 31:815-823), patients with rheumatoid arthritis (RA) (Vuilleumier et al, 2010b, Arthritis Rheum. 62:2640-2650), patients with acute chest pain (Keller et al, 2012, J. Intern. Med. 271:451-462), and patients with severe carotid stenosis (Montecucco et al, 2011, Eur. Heart J. 32:412-421). In MI and RA patients, anti-ApoA-I IgG auto-antibodies were shown to be independently associated with increased risk of CV disease in high CV risk populations (Vuilleumier et al, 2010a and b, supra; Keller et al, 2012, supra), and in patients with severe carotid stenosis they were associated with increased atherosclerotic plaque vulnerability (Montecucco et al, 2011, Eur. Heart J. 32:412-421). Finally, in a recent head-to-head comparison study, anti-ApoA-I IgG auto-antibodies were shown to be the best humoral autoimmune marker for CV prognosis after MI (Vuilleumier, 2011, J. Clinic. Experiment. Cardiology. 2:69), and the only biomarker providing incremental prognostic information to traditional cardiovascular risk factors for CV risk stratification in RA patients (Finckh et al, 2012, Arthritis Care Res (Hoboken) 64:817-825).
From a pathophysiological point of view, anti-ApoA-I IgG auto-antibodies have been shown to be potential mediators of atherogenesis and related complications by increasing atherosclerotic lesions size and vulnerability when administered to ApoE-deficient mice (Montecucco et al, 2011, supra). While these pro-atherogenic effects are not completely understood, there is evidence that they act synergistically at several different levels. Anti-ApoA-I IgG auto-antibodies have been shown (i) to dampen the atheroprotective effects of High Density Lipoprotein (Batuca et al, 2009, Rheumatology (Oxford) 48:26-31), (ii) to promote sterile inflammation through the Toll-like receptor2/CD14 complex (Pagano et al, 2012, J Intern Med. 1365-2796), (iii) to act as a pro-arrythmogenic factors through the mineralocorticoid receptor downstream activation of L-type calcium channels (Rossier et al, 2012, Endocrinology 153:1269-1278), and (iv) to promote neutrophil chemotaxis (Montecucco et al, 2011, supra).
Methods for the prognosis/diagnosis of cardiovascular disorders have been developed, which are based on assessing the presence of anti-ApoA-I auto-antibodies in a subject.
However, these methods are generally based on the immunologic reaction between said antibodies and full-length ApoA-I (Dinu et al, 1998, supra; Vuilleumier et al, 2010a, supra; Keller et al, 2012, supra, Montecucco et al, 2011, supra; Batuca et al, 2009, supra). Major limitations of the use of full length ApoA-I in such diagnostic immunoassays concern the costs to produce large quantities and the instability of the protein which jeopardizes the efficiency of the assay. To solve the problem of the prognostic/diagnostic methods of the prior art, the present invention provides a novel diagnostic immunoassay based on peptides which are less costly to produce, more stable, and which specifically bind to anti-ApoA-I auto-antibodies from patients suffering from cardiovascular diseases. The methods of the invention are particularly useful for electing the therapy appropriate to the patient's specific needs, as well as for taking measures for preventing development of cardiovascular disorders, avoiding first or recurrent cardiovascular events in sub-populations of patients at high cardiovascular risk.